Abstract
Norcantharidin (NCTD), a demethylated analog of cantharidin isolated from blister beetles, has been used as a promising anticancer agent; however, the underlying function of NCTD against human oral squamous cell carcinoma (OSCC) has not been fully understood. Here, this study was aimed to investigate the apoptotic effect and molecular targets of NCTD in human OSCC in vitro and in vivo. The anticancer effects of NCTD and its related molecular mechanisms were evaluated by trypan blue exclusion assay, live/dead assay, western blotting, 4-6-Diamidino-2-Phenylindole (DAPI) staining, flow cytometric analysis, Terminal Deoxynucleotidyl Transferase dUTP Nick end Labeling (TUNEL) assay, and immunohistochemistry. NCTD significantly inhibited cell growth and increased the number of dead cells in HSC-3 and HN22 cell lines. It induced the following apoptotic phenomena: (1) the cleavages of poly (ADP-ribose) polymerase and casepase-3; (2) increase in apoptotic morphological changes (nuclear condensation and fragmentation); (3) increase in annexin V-positive cells or sub-G1 population of cells. NCTD significantly activated the p38 mitogen-activated protein kinase (MAPK) pathway but inactivated the signal transducer and activator of transcription (STAT)3 pathway. A p38 MAPK inhibitor (SB203580) partially attenuated NCTD-induced programmed cell death (apoptosis) in both cell lines, whereas ectopic overexpression of STAT3 did not affect it. NCTD strongly suppressed tumor growth in the tumor xenograft bearing HSC-3 cells, and the number of TUNEL-positive cells increased in NCTD-treated tumor tissues. In addition, NCTD did not cause any histopathological changes in the liver nor the kidney. NCTD induced programmed cell death via the activation of p38 MAPK in OSCC. Therefore, these results suggest that NCTD could be a potential anticancer drug candidate for the treatment of OSCC.
Highlights
Oral Squamous cell carcinoma (OSCC) is a major type of head and neck squamous cell carcinoma (HNSCC) and remains the main cause of HNSCC-associated morbidity and mortality [1]
These results demonstrated that NCTD can promote inhibition of cell growth and induce programmed cell death in OSCC cell lines
NCTD showed no apparent effect on the activation of AKT, extracellular signal-regulated kinase (ERK), and mammalian target of rapamycin (mTOR). These results indicate that p38 mitogen-activated protein kinase (MAPK) and STAT3 may be involved in NCTD-induced programmed cell death in human OSCC cell lines
Summary
Oral Squamous cell carcinoma (OSCC) is a major type of head and neck squamous cell carcinoma (HNSCC) (more than 90%) and remains the main cause of HNSCC-associated morbidity and mortality [1]. The most widely used treatments for managing OSCC include surgery, radiation therapy, and chemotherapy, or any combination of all three [2]. Despite their conceptual promise, more than a third of OSCC patients are often untreatable [3]. Several evidences demonstrated that aberrant activation of STAT3 has been correlated with cell cycle deregulation, enhanced proliferation, and evasion of programmed cell death, as well as adverse clinical parameters in OSCC [7,8]. The role of p38 MAPK and STAT3 in OSCC is still obscure
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